The pregnane X receptor (PXR) regulates the metabolism and excretion of xenobiotics and endobiotics by regulating the expression of drug-metabolizing enzymes and drug transporters. By affecting drug metabolism, changes in the expression levels of PXR target genes can influence the therapeutic and toxicologic response to drugs and cause adverse drug-drug interactions. The activity of PXR is largely regulated by direct ligand binding, and the unique structure of PXR allows the binding of a variety of drugs and prospective drugs. That is, a drug or prospective drug molecule can directly modulate the activity of PXR. As such, PXR is associated with multiple undesired drug-drug interactions.
Treatment of multiple diseases and disorders could be improved if there were available a specific and non-toxic antagonist of PXR is desired. A PXR antagonist would be expected to prevent drug-induced adverse drug effects associated with therapeutic agents that induce the expression of PXR target genes. In particular, a specific and non-toxic PXR antagonist could be used as a co-therapeutic agent to prevent therapy-related toxicities, drug-drug interactions, and drug resistance, and improve therapeutic efficacy and safety. However, due to the “promiscuous” nature of receptor binding (i.e., many drugs bind to and activate PXR) it has been considered extremely difficult to design a PXR antagonist based on structure, and equally difficult to perform SAR studies. As a result, there are currently no specific and non-toxic PXR antagonist exists.
Despite in understanding the biochemistry of PXR, there remains a need for specific and non-toxic antagonists of PXR. These needs and other needs are satisfied by the present invention.